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  • This study focused on NPC L because

    2020-06-30

    This study focused on NPC1L1 because it is critical for intestinal energy metabolism of both dietary and biliary cholesterol.1, 7, 8 Overall, regulation in the intestine of cholesterol, BAs, and lipids by FGF19 and SHP may involve the combined actions of regulation of other genes that were identified in our intestinal RNA-seq analysis of WT and SHP-knockout mice. In addition to regulation of expression of Npc1l1, based on this global analysis and qRT-PCR gene expression studies, SHP may inhibit expression of Acat2 (cholesterol acyltransferase 2), a cholesterol acyltransferase that is important for cholesterol esterification increasing cholesterol absorption efficiency, and Abca1 (adenosine triphosphate–binding cassette transporter A1), which is involved in cholesterol efflux.3, 8, 42 Other examples of genes potentially inhibited by SHP are those involved in sterol biosynthesis, including Hmgcr. Thus, SHP and FGF19 may act as key regulators of multiple sterol metabolism and transport network genes in the intestine, which contributes to maintenance of cholesterol homeostasis. BA composition is important for cholesterol absorption.5, 6, 33 Although hydrophobic bile acids promote sterol absorption, hydrophilic bile acids, such as muricholic acids, inhibit it. In the present study, we observed that relative levels of hydrophilic BAs, particularly tauro-α/β-muricholic acids, were substantially decreased in SHP-knockout mice and that FGF19-mediated changes in BA composition were blunted in these mice, suggesting that SHP and FGF19 not only repress expression of NPC1L1 but also alter BA composition, which may contribute to inhibition of fractional cholesterol absorption. Consistent with increased levels of tauro-α/β-muricholic acids, known FXR antagonists, we observed that FGF19 treatment decreased binding of FXR at Fgf15 and Fgf15 gene expression in an SHP-dependent manner, suggesting that intestinal FXR signaling is feedback-repressed by the FGF19-SHP axis. A recent study has shown that activation of intestinal FXR signaling reduces whole-body cholesterol levels by promoting TICE via increasing hydrophilic BA levels. Further studies will be necessary to examine whether the FGF19-SHP axis can regulate cholesterol levels in part by promoting TICE, as well as by inhibiting intestinal NPC1L1 expression and cholesterol absorption, as shown in the present study. The roles of FGF19 and SHP as regulators of sterol metabolism and transport extend beyond the intestine. Recent SHP ChIP-sequencing studies in livers of FGF19-treated mice showed that SHP inhibits expression of sterol biosynthetic network genes, including Hmgcr, as well as BA synthetic genes. FGF19 and SHP inhibit the hepatic synthesis of cholesterol, thus preventing excess levels of cholesterol, because of the inhibition of BA synthesis from cholesterol. In addition, enterohepatic BA recycling is also important for reducing cholesterol levels by promoting hepatic conversion of cholesterol into BAs, and BA sequestrants that inhibit this recycling have been used for hypercholesterolemia.1, 3, 8, 43 A key ileal BA transporter, Asbt, is important for BA recycling and is inhibited by FGF19 signaling, and high-affinity ASBT inhibitors are alternatives to the sequestrants for treating hypercholesterolemia with reduced adverse effects. In our intestinal RNA-seq analysis, expression of Asbt was increased in SHP-knockout mice. A recent study showed that treatment with an oral ASBT inhibitor that interrupts enterohepatic BA circulation protected against nonalcoholic fatty liver disease in obese mice and resulted in reduced hepatic triglyceride and total cholesterol levels and increased fecal BA levels. Thus, FGF19 and SHP appear to act at both the liver and intestine by targeting multiple network genes important for maintaining sterol and BA homeostasis. In conclusion, this study identifies SHP and FGF19 as new physiological regulators of cholesterol absorption in the intestine, in part by inhibiting the expression of NPC1L1 and by possibly altering BA composition. Endocrine FGF hormones, including FGF19, have great therapeutic potential for treatment of a wide range of human diseases, including metabolic disorders. Furthermore, NPC1L1 is the molecular target of the cholesterol-lowering drug ezetimibe.7, 24 Thus, the intestinal FGF19-SHP-NPC1L1 axis identified in this study may provide new molecular targets for treating hypercholesterolemia and related diseases, including cardiovascular disease, diabetes, and non-alcoholic fatty liver disease.